Lipopolysaccharide results in a marked decrease in hepatocyte nuclear factor 4α in rat liver

被引:46
|
作者
Wang, B
Cai, SR
Gao, CH
Sladek, FM
Ponder, KP
机构
[1] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA
[3] Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA
关键词
D O I
10.1053/jhep.2001.28885
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
The acute-phase response can result in decreased liver-specific functions and death as a result of liver failure. We show here that lipopolysaccharide (LPS), an endotoxin that induces the acute-phase response, results in a marked decrease in the major isoforms of the transcription factor, hepatocyte nuclear factor 4 alpha (HNF-4 alpha), in livers of rats. HNF-4 alpha is a nuclear receptor that is critical for the expression of several liver-specific genes. This decrease in HNF-4 alpha is primarily the result of a posttranscriptional mechanism, because mRNA levels are normal, and there are no major changes in the splicing patterns. This decrease was of functional significance, because expression of a gene that is highly dependent on HNF-4 alpha, HNF-1 alpha, was reduced. Interleukin-1 beta (IL-1 beta) is a cytokine whose levels are increased in vivo in response to LPS. IL-1 beta resulted in a decrease in HNF-4 alpha levels in HepG2 cells. This IL-1 beta -induced decrease was likely caused by degradation via the proteasome, because it was prevented by the addition of the proteasome inhibitor, MG132. We conclude that the decrease in HNF-4 alpha that occurs in vivo after the administration of LPS may be the result of IL-1 beta -induccd degradation, and likely contributes to the liver insufficiency that occurs. IL-1 beta antagonists or proteasome inhibitors might increase HNF-4 alpha protein levels in the acute-phase response, which could result in increased liver function and survival.
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页码:979 / 989
页数:11
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